Over the past two decades, the promise of accelerated drug development and personalized medicine have brought heighten attention to the field of biomarker. But do you really know what biomarker are, how they are developed, and how they are used?
Here, I'll share over 15 years of experience in the fields of biomarker development and translational research to try to answer some of these questions.

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Tuesday, October 18, 2011

Volumetric MRI and Neuropathology in the Elderly: a Key Bridging Study

In the
October 17th issue of PLoS One, Robert Dawe and colleagues, from the
Illinois Institute of Technology and the Rush Alzheimer’s Disease Center, present
the results of a key bridging study of volumetric MRI correlation with normal
aging, Alzheimer’s disease (AD), and additional neuropathologies frequently
associated with aging (link).

As
mentioned in an earlier post (Biomarker
Qualification Consortia: The ADNI Success Story), in vivo volumetric MRI of
specific region of the brain (i.e. medial temporal lobe àhippocampus) has been shown
to be a valuable biomarker of disease progression in AD and mild cognitive
impairment (MCI). While the correlation
between reduction in hippocampal volume and histopathologically confirmed AD
has been conclusively demonstrated, the effect of other neuropathologies generally
associated with aging on hippocampal volume remained ill-defined.

In
order to address this gap in knowledge, the authors combined antemortem imaging
studies, antemortem cognitive testing, postmortem MRI on isolated brain
hemisphere, and histopathology on the brains of 100 elderly subjects from the
Rush Memory and Aging Project, and the Religious Order Study (two longitudinal
clinical-pathologic studies of aging). The
authors confirmed the strong association between reduced hippocampal volume and
the diagnostic of AD (determined prior to death based on cognition test and
determined postmortem based on histopathology).
In addition, hippocampal volume was related to multiple cognitive
abilities assessed proximate to death, with its strongest association with
episodic memory. Other pathologies such
as Lewy bodies, moderate amyloid
angiopathy, gross infarcts, and micro infarcts were not significantly associated
with reduced hippocampal volume. In
contrast, hippocampal
sclerosis (HS) was strongly associated with significant reduction in hippocampal
volume independently of the presence or absence of co-occurring AD pathology
(of 13 individuals with HS, 9 had also AD pathology and 4 had not other
pathology). In fact, the association of
HS and reduced hippocampal volume was more pronounced than that observed in AD.
Shape analysis of the hippocampal
surface confirmed prior knowledge namely that hippocampal volume reduction in
AD is more pronounced in the head and tail of the hippocampus, and that these
changes tend to be more homogeneously distributed in HS. The authors did not discuss whether shape analysis
of the hippocampal surface could be used to distinguish between AD and HS.

Despite
some minor limitations: the postmortem MRI performed on isolated brain
hemispheres precluded the measurement of cranial volume, this study provides a
highly valuable bridge between in vivo volumetric MRI measurements and
underlying neuropathology.